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6-cyclohexylpyrimidone HIV reverse transcriptase inhibitor, preparation method and application thereof

A cyclohexylmethylpyrimidinone and reverse transcriptase inhibition technology, applied in the field of its preparation, 5-isopropyl-2--6-cyclohexylmethylpyrimidinone compounds, can solve drug resistance and side effects , HIV virus is easy to mutate and other problems, to achieve the effect of small cytotoxicity, high selectivity index, and significant anti-HIV-1 virus activity

Inactive Publication Date: 2017-06-20
YUNNAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many reverse transcriptase inhibitors, more new reverse transcriptase inhibitors need to be developed due to serious side effects, HIV virus variability, and drug resistance.

Method used

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  • 6-cyclohexylpyrimidone HIV reverse transcriptase inhibitor, preparation method and application thereof
  • 6-cyclohexylpyrimidone HIV reverse transcriptase inhibitor, preparation method and application thereof
  • 6-cyclohexylpyrimidone HIV reverse transcriptase inhibitor, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0023] Example 1: Synthesis of ethyl 4-cyclohexyl-2-isopropyl-3-oxobutanoate

[0024] Combine 52.4g activated zinc powder and 450ml anhydrous THF in N 2 Add a few drops of ethyl α-bromoisovalerate 2 dropwise under protection to initiate the reaction, reflux and stir at 66°C for 45 minutes until the reaction solution turns dark green, add 20.324g (0.165mol) cyclohexyl acetonitrile at one time, and within 1h Add 2 (88.71g, 0.4243mol) slowly, stop heating after continuing to reflux for 1H, cool to room temperature, add 80ml of 50% K 2 CO 3 The solution was vigorously stirred for 10 min, the reaction solution was allowed to stand and separated, the organic phase was separated, the residue was extracted with THF, the organic phase was combined, 150 ml of 15% HCl was added for hydrolysis, the organic layer was separated and concentrated under reduced pressure, and the aqueous layer was extracted with ethyl acetate for 3 times, the organic phases were combined, washed three times w...

example 2

[0025] Example 2: Preparation of 6-cyclohexyl-5-isopropyl-2-thiouracil

[0026] In a dry reaction flask, add 10g (0.43mol) of sodium metal in 300mL of absolute ethanol in batches, after the sodium is dissolved and cooled, add 24g (0.315mol) of thiourea at one time, and then dropwise add the above compound 3 (0.27mol ) in 20 mL of ethanol solution, heat the mixture to reflux for 5-7 hours, stop heating after TLC tracking until the compound 3 raw material point disappears, cool, evaporate the solvent under reduced pressure, dissolve the residue in 300 mL of water, adjust the pH value with concentrated hydrochloric acid It is about 6, a large amount of white precipitates are produced, filter with suction, wash the filter cake with water, and dry to obtain 6-cyclohexyl-5-isopropyl-2-thiouracil, which can be directly used for the synthesis of the target compound in the next step without purification .

example 3

[0027] Example 3: Preparation of 5-isopropyl-2-(4-hydrocarbylformyloxyphenylcarbonylmethylthio)-6-cyclohexylpyrimidinone compound I

[0028] Dissolve 5-isopropyl-6-cyclohexylmethyl-2-thiouracil (2mmol) in 10ml of dry DMF solution, add K 2 CO 3 (2mmol), stirred and reacted at room temperature for half an hour, added 4-(2-bromoacetyl)phenyl ester 5 (2.2mmol), stirred and reacted at room temperature, TLC tracked until the raw material point disappeared, stopped the reaction, and poured the reaction solution into 50ml of ice water , stirring to precipitate a precipitate, filtering, washing the precipitate with water, suction filtration and drying to obtain a crude product, column chromatography or recrystallization to obtain a pure product.

[0029] Starting from 5-isopropyl-6-cyclohexyl-2-thiol-2,3-dihydropyrimidin-4(1H)-one, following the procedure described above, different 4-(2-bromoacetyl)benzene The ester undergoes alkylation reaction to obtain the I series compounds of th...

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Abstract

The invention belongs to the technical field of drugs, and particularly discloses 5-isopropyl-2-(4-hydrocarbyl methanoyl phenyl carbonyl methylsulfonyl)-6-cyclohexylpyrimidone, N-oxide shown as the formula I, a three-dimensional isomer form, a three-dimensional isomer mixture and a pharmaceutically acceptable salt, a hydrous compound and solvent compound, polycrystals and eutectic crystals, a precursor having a same biological function and a derivative. The compound has significant HIV-1 virus resistant activity, is small in toxicity, high in selectivity index and applicable in relevant drugs for treating AIDS. (Shown in the description).

Description

technical field [0001] The invention belongs to the technical field of medicines, and specifically relates to a class of 5-isopropyl-2-(4-hydrocarbylformyloxyphenylcarbonylmethylthio)-6-cyclohexylpyrimidinone compounds and a preparation method thereof and uses. The compounds have significant anti-HIV-1 virus activity, low toxicity and high selectivity index, and can be used in related drugs for treating AIDS and other diseases. Background technique [0002] At present, the research and development of anti-AIDS drugs is mainly based on the understanding of the life cycle of HIV, and inhibits the replication of HIV virus by blocking all links of its circulation. HIV-1 reverse transcriptase (HIV-1RT) is an essential protein for HIV virus replication. Because of its key role in the transcription of HIV virus mRNA into DNA, it has always been an important target for anti-HIV drug design. Reverse transcriptase inhibitors can be divided into nucleoside reverse transcriptase inhib...

Claims

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Application Information

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IPC IPC(8): C07D239/56C07D405/12A61K31/513A61P31/18
Inventor 何严萍郑永唐张玉芳向思颖张洪彬赵智东杨柳萌
Owner YUNNAN UNIV
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